Network-Related Changes in Neurotransmitters and Seizure Propagation During Rodent Epileptogenesis.

Abstract

OBJECTIVE:

To test the hypothesis that glutamate and GABA are linked to the formation of epilepsy networks and the triggering of spontaneous seizures, we examined seizure initiation/propagation characteristics and neurotransmitter levels during epileptogenesis in a translationally relevant rodent model of mesial temporal lobe epilepsy.

METHODS:

The glutamine synthetase (GS) inhibitor methionine sulfoximine was infused into one of the hippocampi in laboratory rats to create a seizure focus. Long-term video-intracranial EEG recordings and brain microdialysis combined with mass spectrometry were used to examine seizure initiation, seizure propagation, and extracellular brain levels of glutamate and GABA.

RESULTS:

All seizures (n = 78 seizures, n = 3 rats) appeared first in the GS-inhibited hippocampus of all animals, followed by propagation to the contralateral hippocampus. Propagation time decreased significantly from 11.65 seconds early in epileptogenesis (weeks 1-2) to 6.82 seconds late in epileptogenesis (weeks 3-4, paired t test, p = 0.025). Baseline extracellular glutamate levels were 11.6-fold higher in the hippocampus of seizure propagation (7.3 µM) vs the hippocampus of seizure onset (0.63 µM, analysis of variance/Fisher least significant difference, p = 0.01), even though the concentrations of the major glutamate transporter proteins excitatory amino acid transporter subtypes 1 and 2 and xCT were unchanged between the brain regions. Finally, extracellular GABA in the seizure focus decreased significantly from baseline several hours before a spontaneous seizure (paired t test/false discovery rate).

CONCLUSION:

The changes in glutamate and GABA suggest novel and potentially important roles of the amino acids in epilepsy network formation and in the initiation and propagation of spontaneous seizures.

• Authors: Roni Dhaher, Shaun E Gruenbaum, Mani Ratnesh S Sandhu, Sigrid Ottestad-Hansen, Nathan Tu, Yue Wang, Tih-Shih W Lee, Ketaki Deshpande, Dennis D Spencer, Niels Christian Danbolt, Hitten P Zaveri, Tore Eid
• Journal: Neurology (Neurology) Vol. 96 Issue 18 Pg. e2261-e2271 (05 04 2021) ISSN: 1526-632X [Electronic] United States
• PMID: 33722994 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 American Academy of Neurology.

Chemical References

• Neurotransmitter Agents
• Glutamic Acid
• gamma-Aminobutyric Acid

Topics

• Animals
• Brain (metabolism, physiopathology)
• Electroencephalography (methods)
• Glutamic Acid (metabolism)
• Male
• Nerve Net (metabolism, physiopathology)
• Neurotransmitter Agents (metabolism)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Rodentia
• Seizures (metabolism, physiopathology)
• gamma-Aminobutyric Acid (metabolism)